Increasing the histidine ‘density’ in tripodal peptides by gradual N -functionalization of tris (2-aminoethyl)amine (tren) with l -histidyl units: The effect on zinc(II) complexes

Abstract

Abstract Tripodal peptidomimetics have received increasing interest among others as efficient metal ion chelators. Most of these studies have focused on symmetrical, tri-substituted ligands. Our aim was to establish how the increasing donor group ‘density’, i.e. the gradual N-histidyl substitution, alters the coordination chemical properties of the tripodal platform. To this end we synthesized mono- , bis- and tris ( l -histidyl)-functionalized tren derivatives ( L1 , L2 and L3 , respectively), and studied their zinc(II) complexes by pH potentiometry, 1 H NMR and MS spectroscopy. The three ligands provide a variety of donor sites, and consequently different stability and structure for their zinc(II) complexes depending on the pH and metal-to-ligand ratios. In the neutral pH range histamine-like coordination is operating in all cases. Due to the formation of macrochelate between the two/three {N im ,NH 2 } binding sites, L2 and L3 have considerably higher zinc(II) binding ability than histamine, or any other simple peptide with N-terminal His unit. The situation is fundamentally different at higher pH. The tren-like subunit in L1 acts as an anchoring site for amide deprotonation, and the {3NH 2 ,N − ,N tert } type coordination, a rare example where zinc(II)-amide N − coordination takes place, results in outstanding stability. Although L1 provides tight binding above pH 7, it forms only mononuclear species. However, the increasing level of functionalization in L2 and L3 allows the formation of oligonuclear complexes, and at threefold zinc(II) excess the three ligands share nearly the same amount of zinc(II). Moreover, the high histidine ‘density’ in L2 and L3 also provides the formation of imidazolato-bridged structures, which has never been observed before in zinc(II) complexes of simple linear peptides.